As a researcher trained in clinical neurology and basic science with a primary interests in the field of mitochondrial disorders, my principal scientific goal is to better understand the pathogenic mechanisms of this group of diseases and to identify strategies to treat them. My main scientific career goals are to make novel and important contributions to the field of mitochondrial disorders and to satisfy the requirements to become a tenured faculty member in a prestigious academic institution. I believe that the Department of Neurology and Neuroscience at the Weill medical College is an ideal environment to conduct my work and to fulfill my career goals because it provides a fertile ground for scientific growth by allowing interactions with topnotch scientists within the tri-institutional organization that includes Cornell University, Memorial Sloan Kettering, and Rockefeller University. The scope of this proposal is twofold. First, to modulate mitochondrial ATP synthesis in the syndrome NARP (neuropathy ataxia and retinitis pigmentosa) caused by mutations in the mtDNA encoded ATPase 6 (A6). Second, to develop cellular and animal models recapitulating the features of NARP. Such models will serve to investigate in vivo the pathogenic mechanisms underlying mitochondrial disorders and to test therapeutic approaches. Aim 1: NARP cells generate increased free radicals. The mitochondrial respiratory chain is defective presumably due to damage or inhibition and ATP synthesis in NARP cybrid cells can be improved by antioxidants. We will define the mechanisms underlying the respiratory chain dysfunction and test the effects of antioxidants in cells directly derived from NARP patients. Aim 2: We showed that the expression of a wild type A6 protein allotopically from the nucleus improved mitochondrial ATP synthesis in a cybrid model of NARP. The goal is to assess whether allotopic expression of A6 will improve ATP synthesis in patient-derived cells and whether this approach can have a therapeutic use. Aim 3: There are no animal models of NARP. Exogenous mtDNA cannot be transferred into mitochondria to generate transgenic models of NARP. We will test two alternative strategies to generate mutants that recapitulate the biochemical and clinical defects of NARP: a) By allotopic expression from the nucleus of a mutant A6 targeted to normal mitochondria; b) By introducing mutations in a nuclear-encoded mitochondrial protein, ATPase subunit C, at crucial sites of interaction with A6.